Total Synthesis of the Marine Natural Product Hemiasterlin by Organocatalyzed α-Hydrazination

An efficient synthesis of the potently cytotoxic marine peptide hemiasterlin is presented. The tetramethyl-tryptophan moiety is assembled by tert-prenylation of indole, followed by the high-yielding organocatalyzed alpha-hydrazination of a sterically congested aldehyde with excellent enantioselectivity. 2-Bromo-N-ethylpyridinium tetrafluoroborate (BEP)-mediated peptide coupling completes the synthesis, being the first approach that does not employ chiral auxiliaries. A novel phenonium-type rearrangement of the indole system occurred when subjecting dihydroxylated 3-tert-prenylindole to Mitsunobu conditions.